Oncogene-induced senescence (OIS) is a major anti-cancer barrier that inhibits malignant transformation of precancerous cells, in which the p53 signaling plays a central role. Previous studies have shown that p53 induction in precancerous cells is attributed to the ATM-mediated DNA damage response (DDR). Several protein kinases in the DDR, including ATM, CHK1 and CHK2, phosphorylate p53 at multiple serine/threonine sites, which has long been considered to stabilize and activate p53. However, we and other groups found that phosphorylation-deficient p53 mutant exhibited similar protein stability as the wildtype p53, suggesting that DDR-induced phosphorylation events may not be the only major factor for the p53 induction in response to oncogenic stress. The goal of this application is to unravel the oncogene-induced p53 response in mechanistic detail. P53 is tightly controlled at physiological levels by ubiquitination-mediated protein degradation. Much has been studied on the p53-targeting E3 ubiquitin ligases, such as Mdm2, ARF-BP1, and COP1, little is known about the deubiquitination of p53. In a genome-wide screen using a cDNA library of ubiquitin specific peptidases (USPs), we searched for potential USPs for p53 deubiquitination. Intriguingly, as many as 16 USPs significantly inhibited p53, while only 4 USPs moderately increased p53 activity. This result indicated that USPs probably modulate p53 activity primarily through promoting p53 inhibitors, such as E3 ubiquitin ligases. Since all of the p53-targeting E3 ubiquitin ligases are also degraded by auto-ubiquitination, a potential mechanism is that USPs negatively regulate p53 levels via deubiquitination and stabilization of the p53- targeting E3 ligases. This is true in the previously identified USP7-Mdm2-p53 regulatory loop, and is also supported by our current finding that USP4 inhibits p53 by deubiquitination and stabilization of ARF-BP1. Furthermore, p53 is induced upon oncogenic stress even in the absence of detectable DNA damage, suggesting a DDR-independent induction of p53. In this study, we show that oncogene-induced reactive oxygen species (ROS) inactivate the enzymatic activity of USPs through oxidation of crucial cysteine residues in their catalytic pockets, resulting in destabilization of the p53-targeting E3 ligases and consequential stabilization of p53. Based on these results, we propose that USPs function as redox sensor to translate oncogenic stress into the p53 signaling during cancer initiation.